Treating CLL With Immunotherapy: How Is Research Evolving?

Published on
January 25, 2016

Topics include:
Treatment

How do
checkpoint inhibitors apply in CLL? Where
do we stand with CAR-T therapy? From the 2015 American Society of Hematology
(ASH) meeting, CLL expert Dr. William Wierda shares his insights into this
exploding field of research. Dr. Wierda discusses
developing immunotherapy options, including CAR T-cell therapies, which he
feels “…hold the most hope as a curative strategy for CLL….CAR T-cell therapy
is the next step to cure patients with CLL.”

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Hello and welcome to Patient Power. I’m Andrew
Schorr. At the 2015 meeting of the American Society of Hematology, there was a
lot of discussion about CLL. I got to sit down with a leading expert in the
field. That’s Dr. Willam Wierda from MD Anderson Cancer Center in Houston.

I asked him about so-called checkpoint inhibitors. These are
medicines that can manipulate the immune system to fight the cancer. How do
they apply in CLL?

Dr.
Wierda:

The solid tumor field is exploded with these
checkpoint inhibitors. New drugs that
have been approved every week we hear about a new drug that’s been or a drug
that’s been approved in another indication, a new drug approved or a drug
that’s been approved in another indication in the solid tumors. These are antibodies that are directed
against immune-modulating or immune-regulating proteins in T cells and in
antigen-presenting cells.

And when patients with solid tumors have been given these
drugs, they’ve seen remarkable responses—responses where, for example, in
melanoma, patients were not expected to live beyond a year or two, and patients
are living 25 percent of them now are living out beyond three to five
years. So they’re getting exceptional,
very durable responses in the solid tumor setting with these checkpoint
inhibitors. They’ve been slower to come
to the hematologic malignancies. We at [MD]
Anderson have been focused, and I’ve spent the last year working with a
colleague of mine at [MD] Anderson by the name of Nitin Jain on opening
protocols with these agents for patients with CLL.

We have a PD-1 antibody protocol that is now open, and we’re
working on opening a PDL-1. PD-1 is the
checkpoint inhibitor that the antibody binds to. PDL-1 is the live-an that binds to the PD-1,
which is expressed in T cells. So I’m very anxious and optimistic about
this. This has been an area that I’ve
been interested in for 10 years. We
published a paper many years ago on CTLA-4 and how it was overexpressed in
patients with CLL, in the T cells of patients with CLL, and we could by using
antibodies block CTLA-4 and show in the laboratory at least enhanced responses
against the leukemia cells by the T cells.

So this is an area that I’ve been intrigued and interested
in for a number of years. It’s
gratifying to see finally we’re able to start testing these agents in patients
with CLL. So there is one abstract with
a drug called pembrolizumab (Keytruda) that’s being reported here at ASH. The Mayo Clinical Group has evaluated pembrolizumab
in patients with non-Hodgkin’s lymphoma including some patients with CLL and Richter’s
transformation in their reporting activity.
So I’m anxious to get things rolling with these studies and to start
treating patients with the drugs to see what the effects are.

Andrew
Schorr:

I also asked Dr. Wierda about another area of
immuno-oncology, so-called CAR T-cell therapy. A couple years ago, there was a
lot of buzz about that. It’s still continuing. How about an update?

Dr.
Wierda:

So this is another area that I’ve been interestedin for a number of years, as you know,
using these chimeric antigen receptors to redirect T cells to react and
eliminate CLL cells. The proteins that
have been the targets for the receptors included CD-19, and I’ve spent a number
of years working with collaborators, Tom Kipps and Lawrence Cooper at [MD] Anderson,
to develop ROR-1 CAR T-cell strategy.
It’s a new area, it’s a new field. It requires new technology, new
production. So far it’s been a
patient-specific treatment that we have had to develop.

So there [have] been a number of challenges that have slowed
the progress of this that are being addressed, and most of the activity right
now in terms of clinical trials is happening in ALL, patients with acute lymphoblastic
leukemia, with regard to the CD-19 CARS.
There are companies such as Juno and Kitz and Novartis who have opened
multicenter clinical trials with the CD-19 CAR that enrolling patients with ALL
and patients with DLBCL or diffuse large B-cell lymphoma.

These companies have spent most of their resources to
achieve this and to open these studies, and so that is why things have been a
little bit slower I think in CLL because they’ve been focusedso much on opening these studies and
being able to address the enrollment needs for these studies with regard to ALL,
at least for the CD-19 trials. Clearly,
there’s activity with the CAR T-cell strategy in CLL, and that I think will
translate into having a number of clinical trials open once we get past this
phase of having them open and being able to address the needs for the ALL and
DLBCL group.

And the same is true for ROR1, and Juno I know has been
working on ROR1 strategy. We’ve been
working for a number of years. Our
academic efforts are a little bit slower and more challenging, because we don’t
have the same funding as pharmaceutical companies do. And we have to ask [for] and
write grants, and ask for funding to support those, and that cost listing is
down. So the CAR T-cell strategy will
happen. I think it’s a very reasonable
approach. I’m enthusiastic about this
approach as the next treatment for patients with CLL.

It is a treatment right now that does have side effects and
complications that are not insignificant. And so I think that will be another
challenge when we start opening trials and treating patients with CLL with
these CAR-T cells making them more tolerable and just a little bit safer so
that we don’t see the same incidents of severe cytokine-release syndromes that
are seen in the acute leukemia patients for CLL then it’ll become a more viable
approach and strategy. That’s a
challenge if you have a patient who’s doing well on an ibrutinib (Imbruvica) if
you’re talking about a treatment that 25 percent of patients have a severe
reaction it’s a difficult approach.

I think it could potentially be—it’s among the treatment
strategies that are in development. The
CAR T-cell strategy right now I hold the most hope for as a curative strategy
for CLL. I’m enthusiastic about the CAR
T-cell and cellules therapy as the next step to cure patients with CLL or
potentially one of the next steps. It
works by a different mechanism of action.
Transplant we know is a cell-based strategy that we can eliminate
disease and potentially cure them long term.
And so the mechanism of action is similar with the CAR T as it is with
transplant, because you’re using immune cells to eliminate the leukemia
cells. So I hold the most hope right now
for cure of the disease with immune-based strategies, CAR T-cell strategies,
perhaps the checkpoint inhibitors will see what the data looks like for the checkpoint
inhibitors.

Andrew
Schorr:

Finally, I asked Dr. Wierda his perspective on
how he thinks patients should be feeling about CLL today with the approved
medicines and others that are very promising.

Dr.
Wierda:

Today, I think for me the challenge in terms of
research and what we do is how are we gonna cure patients? We have so many
treatment options available. There are
drugs that have non-overlapping toxicities that work by different mechanism of
actions, and we know information about how patients do, and they do
exceptionally well long term when we use those agents alone. We haven’t even really started those trials
using combinations or using sequencing of these agents.

So I’m very optimistic and very sure and can very adamantly
state that we can control the disease with the agents that we have long term. So the outlook has never been better for
patients with CLL. We can control the
disease long term with these slow molecule inhibitors. We still have chemo and immunotherapy which
is very active as a fallback. Or if we need to, we can resort to chemo
immunotherapy. But with the small molecule inhibitors, we have tools that can
manage the disease for very long periods of time. And again, right now my intent and research
that we’re doing and my efforts are gonna all be directed at how can we cure
patients.

How can we get rid of those last CLL cells that are there so
that patients don’t have to worry about the disease? They can be off treatment. Their immune system can reconstitute, renormalize,
we don’t have to worry about infection, and they can go back to living a normal
life.

Andrew
Schorr:

Thanks to Dr. William Wierda for joining us again
on Patient Power and for sharing his perspective to give us all hope. Be sure
to be a member of our CLL community, so you’ll always know when we post
something new. I’m Andrew Schorr. Remember, knowledge can be the best medicine
of all.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

At the ASH 2015 meeting, CLL expert Dr. Jan Burger discussed the results from the RESONATE-2 trial, which studied the use of ibrutinib (Imbruvica) vs. chlorambucil in the frontline setting in patients over 65.